Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma.
Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma.
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DOI：
10.1186/1748-717x-8-65
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发表时间：
2013-03-19
期刊：
影响因子：
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通讯作者：
Kirkby NF
中科院分区：
文献类型：
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作者：
Barazzuol L;Jena R;Burnet NG;Meira LB;Jeynes JC;Kirkby KJ;Kirkby NF
放疗和化疗的细胞毒性可以通过调节DNA修复来增强。 PARP 是有效碱基切除修复 DNA 单链断裂所需的酶家族，抑制 PARP 可以阻止这些损伤的修复。目前的研究探讨了 ABT-888（一种 PARP1-2 的有效抑制剂）、电离辐射和基于替莫唑胺 (TMZ) 的化疗在胶质母细胞瘤 (GBM) 细胞中的三模式组合。将四种人 GBM 细胞系用 5 μM ABT-888 处理 5 小时，然后同时暴露于 X 射线和 5 或 10 μM 剂量的 TMZ 2 小时。使用聚（ADP-核糖）（pADPr）的免疫检测来测量 ABT-888 的 PARP 抑制。通过克隆形成测定以及细胞和细胞核的形态学表征来检查细胞存活和不同的细胞死亡途径。将 ABT-888 与辐射结合可增强所有四种细胞系的细胞杀伤效果，如 50% 存活率 (SER50) 范围内的 1.12 至 1.37 之间的敏化剂增强比率所证明的那样。当 ABT-888 在 O6-甲基鸟嘌呤-DNA-甲基转移酶 (MGMT) 甲基化细胞系中与 X 射线和 TMZ 联合使用时，放射和化学敏化作用进一步增强，SER50 高达 1.44。在一种 MGMT 非甲基化细胞系中也测量了这种效应，其 SER50 值为 1.30。还考虑了 ABT-888、TMZ 和 X 射线诱导细胞凋亡，并且 ABT-888 对凋亡细胞数量的影响在以后的时间点很明显。此外，这项工作表明，ABT-888介导的致敏作用是复制依赖性的，从而证明这种效应在肿瘤细胞中可能更为明显，因为肿瘤细胞中内源性复制损伤的比例比正常细胞更大。这项研究表明，ABT-888 与传统的放化疗结合，具有增强当前 GBM 标准治疗的临床潜力。有趣的是，我们的结果表明，对于那些肿瘤未甲基化且目前从 TMZ 获益较少的患者，使用 PARP 抑制剂可能具有临床意义。
The cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells. Four human GBM cell lines were treated for 5 h with 5 μM ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 μM for 2 h. ABT-888′s PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus. Combining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells. This study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.